Heterocyclic compounds

ABSTRACT

The present invention relates to a compound (3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid methods for use of this and other compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional of copending application Ser. No. 15/034,661 filedon May 5, 2016 which is a 371 of International Application ofPCT/IN2014/000704 filed, on 3 Nov. 2014, which designated the U.S.,claims the benefit thereof and incorporates the same by reference.

FIELD OF INVENTION

The present invention relates to novel GPR 40 agonists of the generalformula (I), their tautomeric forms, their stereoisomers, theirpharmaceutically acceptable salts, pharmaceutical compositionscontaining them, methods for their preparation, use of these compoundsin medicine and the intermediates involved in their preparation.

The present invention is directed to G-protein coupled receptor (GPCR)agonists that are useful for the treatment of obesity, diabetes andrelated metabolic disorders.

The compounds of the general formula (I) lower blood glucose, regulateperipheral satiety, lower or modulate triglyceride levels and/orcholesterol levels and/or low-density lipoproteins (LDL) and raises thehigh-density lipoproteins (HDL) plasma levels and hence are useful incombating different medical conditions, where such lowering (andraising) is beneficial. Thus, it could be used in the treatment and/orprophylaxis of obesity, hyperlipidemia, hypercholesteremia,hypertension, atherosclerotic disease events, vascular restenosis,diabetes and many other related conditions.

The compounds of general formula (I) are useful to prevent or reduce therisk of developing atherosclerosis, which leads to diseases andconditions such as arteriosclerotic cardiovascular diseases, stroke,coronary heart diseases, cerebrovascular diseases, peripheral vesseldiseases and related disorders.

These compounds of general formula (I) are useful for the treatmentand/or prophylaxis of metabolic disorders loosely defined as Syndrome X.The characteristic features of Syndrome X include initial insulinresistance followed by hyperinsulinemia, dyslipidemia and impairedglucose tolerance. The glucose intolerance can lead to non-insulindependent diabetes mellitus (NIDDM, Type 2 diabetes), which ischaracterized by hyperglycemia, which if not controlled may lead todiabetic complications or metabolic disorders caused by insulinresistance. Diabetes is no longer considered to be associated only withglucose metabolism, but it affects anatomical and physiological,parameters, the intensity of which vary depending upon stages/durationand severity of the diabetic state. The compounds of this invention arealso useful in prevention, halting or slowing progression or reducingthe risk of the above mentioned disorders along with the resultingsecondary diseases such as cardiovascular diseases, likearteriosclerosis, atherosclerosis; diabetic retinopathy, diabeticneuropathy and renal disease including diabetic nephropathy,glomerulonephritis, glomerular sclerosis, nephrotic syndrome,hypertensive nephrosclerosis and end stage renal diseases, likemicroalbuminuria and albuminuria, which may be result of hyperglycemiaor hyperinsulinemia.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorderscharacterized by abnormal glucose homeostasis resulting in elevatedblood sugar. There are many types of diabetes, but the two most commonare Type I (also referred to as insulin-dependent diabetes mellitus orIDDM) and Type II (also referred to as non-insulin-dependent diabetesmellitus or NIDDM).

The etiology of the different types of diabetes is not the same;however, everyone with diabetes has two things so common: overproductionof glucose by the liver and little or no ability to move glucose out ofthe blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either don't produce insulin or can'tefficiently use the insulin they produce; therefore, they can't moveglucose into their cells. Glucose accumulates in the blood creating acondition called hyperglycemia, and over time, can cause serious healthproblems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

About 5% to 10% of the people who have diabetes have IDDM. Theseindividuals don't produce insulin and therefore must inject insulin tokeep their blood glucose levels normal. IDDM is characterized by low orundetectable levels of endogenous insulin production caused bydestruction of the insulin-producing β cells of the pancreas, thecharacteristic that most readily distinguishes IDDM from NIDDM. IDDM,once termed juvenile-onset diabetes, strikes young and older adultsalike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM).NIDDM subjects, produce insulin, but the cells in their bodies areinsulin resistant; the cells don't respond properly to the hormone, soglucose accumulates in their blood. NIDDM is characterized by a relativedisparity between endogenous insulin production and insulinrequirements, leading to elevated blood glucose levels. In contrast toIDDM, there is always some endogenous insulin production in NIDDM; manyNIDDM patients have normal or even elevated blood insulin levels, whileother NIDDM patients have inadequate insulin production (Rotwein, R. etal. N. Engl. J. Med. 308, 65-71 (1998)). Most people diagnosed withNIDDM are age 30 or older, and half of all new cases are age 55 andolder. Compared with whites and Asians, NIDDM is more common amongNative Americans, African-Americans, Latinos, and Hispanics. Inaddition, the onset can be insidious or even clinically non-apparent,making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many havesuggested that primary insulin resistance of the peripheral tissues isthe initial event. Genetic epidemiological studies have supported thisview. Similarly, insulin secretion abnormalities have been argued as theprimary defect in NIDDM. It is likely that both phenomena are importantcontributors to the disease process (Rimoin, D. L., et. al. Emery andRimoin's Principles and Practice of Medical Genetics 3^(rd) Ed.1:1401-1402 (1996)).

Many people with NIDDM have sedentary lifestyles and are obese; theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

The G-protein-coupled receptor GPR 40 functions as a receptor forlong-chain free fatty acids (FFAs) in the body and as such is implicatedin a large number of metabolic conditions in the body. For example ithas been alleged that a GPR 40 agonist promotes insulin secretion whilsta GPR 40 antagonist inhibits insulin secretion and so depending upon thecircumstances the agonist and antagonist may be useful as therapeuticagents for the number of insulin related conditions such as type 2diabetes, obesity, impaired glucose tolerance, insulin resistance,neurodegenerative diseases and the like.

There is increasing evidences that lipids can also serve asextracellular ligands for a specific class of receptors and thus act as“nutritional sensors” (Nolan C J et al. J. Clinic. Invest., 2006, 116,1802-1812. The free fatty acids can regulate cell function. Free fattyacids have demonstrated as ligands for orphan G protein coupledreceptors (GFCRs) and have been proposed to play a critical role inphysiological glucose homeostasis.

GPR40, GPR120, GPR41 ad GPR43 exemplify a growing number of GPCRs thathave been shown to be activated by free fatty acids. GPR40 and GPR120are activated by medium to long-chain free fatty acids whereas GPR 41and GPR 43 are activated by short-chain fatty acid (Brown A J et al,2003).

GPR 40 is highly expressed on pancreatic β-cells, and enhancesglucose-stimulated insulin secretion (Nature, 2093, 422, 173-176, J.Bio. Chem. 2003, 278, 11303-11311, Biochem. Biophys. Res. Commun. 2003,301, 406-410).

Free fatty acids regulate insulin secretion from pancreatic β cellsthrough GPR40 is reported (Lett. to Nature 2003, 422, 173-176).

GlaxoSmithKline Research and Development, US published an article inBioorg. Med. Chem. Lett. 2006, 16, 1840-1845 titled Synthesis andactivity of small molecule GPR40 agonists. (Does this describe GW9508?)Another article titled Pharmacological regulation of insulin secretionin MIN6 cells through the fatty acid receptor GPR40: Identification ofagonist and antagonist small molecules is reported in

Br. J. Pharmacol. 2006, 148, 619-928 from GlaxoSmithKline, USA (Doesthis describe GW9508?)

Solid phase synthesis and SAR of small molecule agonists for the GPR 40receptor is published in Bioorg. Med. Chem. Lett. 2007, 16, 1840-1845 byGlaxo SmithKline Res. & Dev. USA, including those with the followingstructures.

Johnson & Johnson Pharmaceutical Research and development, USA published“Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propanoicacid as a Novel Series of G-protein-coupled receptor 40 agonists (J.Med. Chem. 2007, 16, 2807-2817)

National Institutes of Health, Bethesda, Maryland published“Bidirectional Iterative Approach to the Structural Delineation of theFunctional Chemo print in GPR 40 for agonist Recognition (J. Med. Chem.2007, 50, 2981-2990).

Discovery of diacyl phloroglucinols of the following formula

as a new class of GPR40 (FFAR1) agonists has been published by Piramallife Sciences, Ltd. in Bioorg. Med. Chem. Lett. 2088, 18, 6357-6361

Synthesis and SAR of 1,2,3,4-tetrahydroisoquinoline-1-ones as novelG-protein coupled receptor40(GPR40) antagonists of the following formulahas been published in Bioorg. Med Chem. Lett. 2009, 19, 2400-2403 byPfizer

Piramal Life Sciences Ltd. published “Progress in the discovery anddevelopment of small molecule modulators of G-protein coupled receptor40(GPR40/FFA1/FFAR1) an emerging target for type 2 diabetes” in Exp.Opin. Therapeutic Patents 2009, 19(2), 237-264.

There was a report published in Zhongguo Bingli Shengli Zazhi 2009,25(7), 1376-1380 from Sun Yat. Sen University, Guangzhou, which mentionsthe role GPR 40 on lipoapoptosis.

A novel class of antagonists for the FFA's receptor GPR 40 was publishedin Biochem. Biophy. Res. Commun. 2009, 390, 557-563.

Merck Res. Laboratories published “Discovery of5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists” having thefollowing formula in Bioorg. Med. Chem. Lett. 2010, 20, 1298-1301

Discovery of TAK-875, a potent, selective, and orally bioavailable GPR40 agonist is reported by Takeda Pharmaceutical Ltd. ACS Med. Chem.Lett. 2010, 1(6), 290-294

In another report from University of Southern Denmark“Structure—Activity of Dihydrocinnamic acids and discovery of potentFFA1 (GPR40) agonist TUG-469” is reported in ACS Med. Chem. Lett. 2010,1(7), 345-349.

The free fatty acid 1 receptor (FFAR1 or GPR40), which is highlyexpressed on pancreatic β-cells and amplifies glucose-stimulated insulinsecretion, has emerged as an attractive target for the treatment of type2 diabetes (ACS Med. Chem. Lett. 2010, 1(6), 290-294).

G-protein coupled receptor (GPR40) expression and its regulation inhuman pancreatice islets: The role of type 2 diabetes and fatty acids isreported in Nutrition Metabolism & Cardiovascular diseases 2010, 20(1),22-25

Ranbaxy reported “Identification of Berberine as a novel agonist offatty acid receptor GPR40” in Phytother Res. 2010, 24, 1260-63.

The following substituted 3-(4-aryloxyaryl)-propanocic acids as GPR40agonists are reported by Merck Res. Lab. in Bioorg. Med. Chem. Lett.2011, 21, 3390-3394

CoMSIA study on substituted aryl alkanoic acid analogs as GPR 40agonists is reported Chem. Bio. Drug. Des. 2011, 77, 361-372

Takeda further published “Design, Synthesis and biological activity ofpotential and orally available G-protein coupled receptor 40 agonists”in J. Med. Chem. 2011, 54(5), 1365-1378.

Amgen disclosed a potent orally bioavailable GPR 40 agonist AMG-837 inBioorg. Med Chem, Lett. 2012, 22, 1267-1270

Discovery of phenylpropanoic acid derivatives containing polarfunctionalities as Potent and orally bioavailable G protein-coupledreceptor 40 Agonist for the treatment of type 2 Diabetes is reported inJ. Med. Chem. 2012, 55, 3756-3776 by Takeda.

Discovery of AM-1638: A potent and orally bioavailable GPR40/FFA1 fullagonist is reported in ACS Med. Chem. Lett. 2012, 3(9), 726-730.

Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic acids: Discoveryof a Non-free Fatty acid like, highly bioavailable G protein-coupledreceptor 40/free acid receptor 1 agonist as a glucose-dependentinsulinotropic agent is reported by Takeda in J. Med. Chem. 2012, 55,3960-3974.

Bayer disclosed indane, dihydrobenzofuran, and tetrahydronaphthalenecarboxylic acid derivatives and their use as antidiabetics in patentapplication no. WO 2004011446 with the following formulae

Takeda disclosed 3-(4-Benzyloxyphenyl) propanoic acid derivatives in apatent WO 2005063729 with the following general formula:

WO 2005086661 A1 (22 Sep. 2005, Amgen Inc.) disclosed compounds,pharmaceutical compositions and methods for use in treating metabolicdisorders, having the following formula:Q-L¹-P-L²-M-X-L³-A

US 2006/0004012, Akerman et al. disclosed certain compounds,pharmaceutical compositions and methods for use in treating metabolicdisorders, the said compounds being GPR 40 agonists.

WO 06/038738 A1 (13 Apr. 2006, Takeda Pharmaceutical Ltd., Japan)disclosed certain receptor function regulating agent with the followinggeneral structure

Merck & Co. disclosed antidiabetic bicyclic compounds in WO2006083781.Disclosed therein are bicyclic compounds containing a phenyl or pyridylring fused to a cycloalkyl or heterocyclic ring, to which is attached a5-membered heterocyclic ring, including pharmaceutically acceptablesalts and prodrugs thereof, as agonists of G protein coupled receptor40(GPR40) and are useful as therapeutic compounds, particularly in thetreatment of Type 2 diabetes mellitus, and of conditions that are oftenassociated with the disease, including obesity and lipid disorders, suchas mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia,and hypertriglyceridemia are disclosed.

Merck & Co., in another patent application WO 2006083612 disclosedantidiabetic bicyclic compounds, wherein, the bicyclic compounds containa fused pyridine ring including pharmaceutically acceptable salts andprodrugs thereof, as agonists of G protein coupled receptor 40 (GFR40)and are useful as therapeutic compounds, particularly in the treatmentof Type 2 diabetes mellitus, and of conditions that are often associatedwith the disease, including obesity and lipid disorders, such as mixedor diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, andhypertriglyceridemia. The compounds disclosed in the patent applicationhas the following general structure:

wherein Z is selected from the group consisting of CR₃R₄CO₂R₅,—OCR₃R₄CO₂R₅, N (R₆) (CR₃R₄CO₂R₅), —SCR₃R₄CO₂R₅, tetrazole, and theheterocyclic ring II.

Condensed ring compounds have been disclosed by Yasum et al. in a U.S.Pat. No. 7,820,837. The following formula mentioned, in U.S. Pat. No.7,517,910 claims compounds having a GPR 40 receptor function modulatingaction, which are useful as insulin secretagogues, agents for theprophylaxis or treatment of diabetes and the like

Novel Spiropiperidine compounds have been mentioned by Eli Lilly &Company in WO 2011066183

Eli Lilly also disclosed the following Spiropiperidines in patentapplication no. US20110092531

Novel 1,2,3,4-tetrahydroqiunoline derivatives useful for the treatmentof diabetes have been described by Eli Lilly & Company in patentapplication no. WO 2013025424

A patent application, WO 2013147443 titled “Preparation of β-substitutedcarboxylic acid derivatives for the treatment of diabetes” has beenpublished by Daichi Sankyo.

Piramal Enterprises Limited has published a patent application no. WO2013/128378 for phenyl alkanoic acid derivatives as GPR agonists withthe structure below

Boehringer Ingelheim has published patent application numbers WO2013/144097 & WO 2013/144098 titled “New indanyloxy dihydrobenzofuranylacetic acid derivatives and their use as GPR receptor agonists” with thestructures defined below

Novel therapeutic target for treatment of cancers and related therapiesand methods are disclosed in patent application no. WO 2014145817 byChildren's Medical Center Corporation.

WO 2014146604 disclosed certain fused ring compounds having GPR40receptor function regulating action.

Tricyclic compound and use thereof has been published by SK ChemicalsCo., Ltd. in patent application no. WO2014133361.

Certain antidiabetic bicyclic compounds have been disclosed in patentapplication no. WO2014130608.

Boehringer Ingelheim International disclosed certain other indanyloxydihydrobenzofuranyl acetic acids in patent application nos.WO2013164292, WO2014122067, WO2014086712, and WO2014082918 &US20140148462, US20140221349 & US20140163025.

Takeda Pharmaceutical Company Limited have disclosed, fused cycliccompounds as GPR40 receptor modulators in a patent application no.EP2743268. Bristol-Myers Squibb has disclosed Dihydropyrazole GPR40modulators in patent application nos. WO2014078611, WO2014078610,WO2014078609 & WO2014078608.

LG Life Sciences Limited has disclosed certain GFR40 receptor agonist inpatent WO2014073904. Hancke Orozco et al. have disclosed compounds,compositions, and methods for decreasing intestinal glucose uptake andinducing incretin release in patent application no. US20140128333. MerckSharp & Dohme Corp. disclosed antidiabetic tricyclic compounds inpatents application nos. US20140045746, WO2014022528 and in anotherapplication disclosed certain bridged and fused antidiabetic compoundsin patent US 20140038970.

Novel fluoro-substituted compounds capable of modulating the G-proteincoupled receptor

GPR40 have been disclosed in patent application no. US20140058125.

Mochida Pharmaceutical Co. has disclosed Cyclic amide derivative inpatent US20140057871. Negoro et al. have disclosed certain carboxylicacid compounds in patent application no. US20120035196. Several otherpatent applications have disclosed a varied number of compounds as GPR40modulators. Some of the representative literature is provided below:

Chandra Sekhar Gudla et al have disclosed some new 3-substituted3-(aryloxyaryl)-propanoic acid in IJCPS, 2014, Vol. 2(5), 852-861.

WO 2005095338, WO 2006038738, WO 2006083612, WO 2006083781, WO2007013679, WO 2007136572, WO 2007136573, WO 2007049050, WO 20070123225,WO 2008002931, WO 2008054674, WO 2008054675, WO 200830520, WO2008130514, WO 2008139987, WO 2009058237, WO 2009048527, WO 2009054423,U.S. Pat. No. 7,968,552, WO 2009038204, WO 2010045258, WO 2010012650, WO2010085522, WO 2010085525, WO 2010085528, WO 2010091176, WO 2011044073,WO 2011052756, WO 2011078371, WO 2011069958, WO 2011083752, WO2012111849, WO 2012108478, WO 2012074126, WO 2012020738, WO 2012004261,WO 2012010413, WO 2012010413, WO 2012011125 EP 1731505 A1, WO2011/046851, WO 2014/171762 A1, etc.

Drugs aimed at the pathophysiology associated with insulin dependentType I diabetes and non-insulin dependent Type II diabetes have manypotential side effects and do adequately address the dyslipidemia andhyperglycemia in a high proportion of patients. Treatment is oftenfocused at individual patient needs using diet, exercise, hypoglycaemicagents and insulin, but there is a continuing need for novelantidiabetic agents, particularly ones that may be better tolerated withfewer adverse effects.

Similarly, metabolic syndrome (syndrome X) which is characterized byhypertension and its associated pathologies including atherosclerosis,lipidemia, hyperlipidemia and hypercholesterolemia have been associatedwith decreased insulin sensitivity which can lead to abnormal bloodsugar levels when challenged. Myocardial ischemia and microvasculardisease is an established morbidity associated with untreated or poorlycontrolled metabolic syndrome.

There is a continuing need for novel antiobesity and antidiabeticagents, particularly ones that are well tolerated with few adverseeffects.

The present invention is directed to agonists of GPR 40 that are usefulfor the treatment of diabetes. In humans, GPR 40 is expressed in thepancreas. As discussed above, several GPR 40 agonists have beendeveloped and are continuing to be developed. However, the therapeuticpotential of these compounds to treat diseases has not yet been provedand so there remains the need to develop newer medicines which arebetter or of comparable efficacy with the present treatment regimes,have lesser side effects and require a lower dosage regime.

We herein disclose novel compounds of formula (I) useful asantidiabetic, anti-obesity, hypolipidaemic, hypolipoproteinemic, andantihyperglycemic agents which may have beneficial effect in thetreatment and/or prophylaxis of diseases caused by hyperlipidemia,diseases classified under Syndrome X and atherosclerosis, and methodsfor their preparation.

SUMMARY OF THE INVENTION

The main objective of the present invention is to provide novel GPR40agonists represented by the general formula (I), their tautomeric forms,their stereoisomers, their pharmaceutically acceptable salts, andpharmaceutical compositions containing them or their mixtures thereof.

In an embodiment of the present invention is provided processes for thepreparation of compounds, represented by the general formula (I), theirtautomeric forms, their stereoisomers, their pharmaceutically acceptablesalts.

In a further embodiment of the present invention is providedpharmaceutical compositions containing compounds of the general formula(I), their tautomeric forms, their stereoisomers, their pharmaceuticallyacceptable salts, or their mixtures combination with suitable carriers,solvents, diluents and other media normally employed in preparing suchcompositions.

In yet another embodiment is provided a pharmaceutical compositioncomprising the compound of formula (I) and a second suitable therapeuticagent for the treatment of diabetes, obesity and other relateddisorders.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to compounds of the generalformula (I)

their tautomeric forms, their stereoisomers, their pharmaceuticallyacceptable salts, and pharmaceutical compositions containing themwherein

each of R₁, R₂, R₃, R₄, R₅, R₆, at each occurrence independentlyrepresents H, halogen, hydroxyl, CN, NO₂, CHO, COOH, CO, optionallysubstituted groups selected from, alkyl, alkoxy, thiol, sulphoxide,sulphone, acyl, NH₂ or optionally substituted NHCO-linear or branched(C₁-C₆)alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,hetererocyclylalkyl, heteroaryl, heteroaralkyl or the groups OR, C(O)OR,C(O)R, and SO₂R wherein ‘R’ at each occurrence independently representsoptionally substituted groups selected from H, linear or branched(C₁-C₆)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,hetrerocyclylalkyl, heteroaryl, heteroaralkyl groups; In an alternateembodiment, R₃ and R₄ together may form an oxo group;

‘A’ is selected from 3-7 member partially saturated, unsaturated orsaturated ring which may further be having one or more than oneheteroatom selected from O, S, or N;

Each of ‘E’ & ‘D’ may independently be either nitrogen or carbon. ‘F’may be selected from C, N or O; ‘G’ may be present or absent and whenpresent represents either a bond or is selected from O, S, NR_(a),wherein ‘R_(a)’ represents linear or branched (C₁-C₆) alkyl;

m=1-3; each of ‘n’, ‘r’, ‘p’ and ‘s’ independently represents an integerranging from 0 to 6; q=0-4;

‘X’ may be present or absent and when present is selected from CH₂, O,S, and NR_(a), SO₂NH; wherein R_(a) is as defined earlier;

‘T’ is selected from oxygen, —NH, S, SO, SO₂ or NR_(a), wherein R_(a) isas defined earlier; each of R₇ and R₈ independently may be selected(C₂-C₄)alkyne, nitrile, or a cycloalkyl; Alternatively R₇ and R₈ maycombine with the carbon atom to which it is attached to form a 3-7membered cyclic ring which may optionally further have one or more thanone heteroatom selected from S, N, or O;

R₉ & R₁₀ may be selected from hydrogen, alkyl, alkoxy, and halogengroups.

A preferred embodiment of the present invention relates to compound ofthe general Formula (I′)

their tautomeric forms, their stereoisomers, their pharmaceuticallyacceptable salts, and pharmaceutical compositions containing themwherein

Each of R₁, R₂, R₃ and R₄ occurrence independently represents H,halogen, hydroxyl, CN, NO₂, CHO, COOH, CO, optionally substituted groupsselected from, alkyl, alkoxy, thiol, sulphoxide, sulphone, acyl, NH₂ oroptionally substituted NHCO-linear or branched (C₁-C₆)alkyl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, hetererocyclylalkyl,heteroaryl, heteroaralkyl or the groups OR, C(O)OR, C(O)R, and SO₂Rwherein ‘R’ at each occurrence independently represents optionallysubstituted groups selected from H, linear or branched (C₁-C₆)alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,hetretocyclylalkyl, heteroaryl, heteroaralkyl groups;

In an alternate embodiment, R₃ and R₄ together may form an oxo group;

‘A’ is selected from 3-7 member partially saturated, unsaturated orsaturated ring which may further be having one or more than oneheteroatom selected from O, S, or N;

Each of ‘E’ & ‘D’ may independently be either nitrogen or carbon. ‘F’may be selected from C, N or O;

Each of ‘n’, ‘r’ and ‘s’ independently represents an integer rangingfrom 0 to 6; each of R₅ and R₆ independently may be selected(C₂-C₄)alkyne, nitrile, or a cycloalkyl; Alternatively R₅ and R₆ maycombine with the carbon atom to which it is formed to form a 3-7membered cyclic ring which may optionally further have one or more thanone heteroatom selected from S, N, or O;

The preferred heterocycles representing

may be selected from the following bicyclic rings mentioned below

The substituent —COOH may be optionally replace wherever possible withbioisosteric replacements such as:

and the like;

When any of the groups from R₁ to R₁₀ are substituted with one or manygroups, the substituents may be independently selected from the groupscomprising hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, orsubstituted or unsubstituted groups selected from amidino, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl,heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl,acyloxy, acylamino, monosubstituted or disubstituted amino, arylsmino,aralkylamino, carboxylic acid and its derivatives such as esters andamides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio,alkylsulfonylamino, alkylsulfonyloxy, alkoxycabonylamino,aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino,alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfenylderivatives, sulfonyl derivatives, sulfonic acid and its derivatives.

The aryl group may be an aromatic system containing one, two or threerings wherein such rings may be attached together in a dependent manneror may be fused; in a preferred embodiment such aryl group may beselected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenylgroups;

The heteroaryl group represents 5 to 8 membered aromatic radicals, whichmay be single or fused containing one or more hetero atoms selected fromO, N or S; in a preferred embodiment such groups may be selected frompyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl,imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl,indolinyl, indolyl, azaindolyl, azaindolinyl, benzodihydrofuranyl,benzodihydrothienyl, pyrazolopyrimidinyl, pyrazolopyrimidonyl,azaquinazolinyl, azaquinazolinoyl, pyridofuranyl, pyridothienyl,thienopyrimidyl, thienopyrimidonyl, quinolinyl, pyrimidinyl, pyrazolyl,quinazolinyl, quinazolonyl, pyrimidonyl, pyridazinyl, triazinyl,benzoxazinyl, benzoxazinonyl, benzothiazmyl, benzothiazinonyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl,phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl,phenoxazinyl groups;

The term “heterocyclyl” represents saturated, partially saturated orunsaturated ring-shaped radicals, the heteroatoms being selected fromnitrogen, sulfur or oxygen; in a preferred embodiment such groups may beselected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl,2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl,2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl,oxazolidinyl, thiazolidinyl, and the like; examples of partiallysaturated heterocyclic radicals include dihydrothiophene, dihydropyran,dihydrofuran, dihydrothiazole groups.

The “alkyl” group used either alone or in combination with otherradicals, denotes a linear or branched radical containing one to sixcarbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like;

-   -   the “alkenyl” group used either alone or in combination with        other radicals, is selected from a radical containing from two        to six carbons, more preferably groups selected from vinyl,        allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,        2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the “alkenyl”        group includes dienes and trienes of straight and branched        chains;    -   the “alkynyl” group used either alone or in combination with        other radicals, is selected from a linear or branched radical        containing two to six carbon atoms, more preferably thienyl,        1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,        1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and        the like. The term “alkynyl” includes di- and tri-ynes;    -   the “cycloalkyl” or “alicyclic” group used either alone or in        combination with other radicals, is selected from a cyclic        radical containing three to six carbons, more preferably        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;        The terms “bicycloalkyl” means more than one cycloalkyl groups        fused together;    -   the “cycloalkenyl” group used either alone or in combination        with other radicals, are preferably selected from cyclopropenyl,        1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl,        2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl 2-cyclohexenyl,        3-cyclohexenyl and the like;    -   the “alkoxy” group used either alone or in combination with        other radicals, is selected from groups containing an alkyl        radical, as defined above, attached directly to an oxygen atom,        more preferably groups selected from methoxy, ethoxy, n-propoxy,        iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy,        hexyloxy, and the like;    -   the “cycloalkoxy” group used either alone or in combination with        other radicals, is selected from groups containing an cycloalkyl        radical, as defined above, attached directly to an oxygen atom,        more preferably groups selected from cyclopropoxy, cyclobuloxy,        cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like;    -   the “aryloxy” group used either alone or in combination with        other radicals, is selected from groups containing an aryl        radical, as defined above, attached directly to an oxygen atom,        more preferably groups selected from phenoxy, naphthyloxy,        tetrahydronaphthyloxy, biphenyloxy, and the like;    -   the “aralkyl” group used either alone or in combination with        other radicals, is selected from groups containing an aryl        radical, as defined above, attached directly to an alkyl        radical, as define above, more preferably groups selected from        benzyl, phenethyl, and the like;    -   the “aralkoxy” group used either alone or in combination with        other radicals, is selected from groups containing an aralkyl        radical, as defined above, attached directly to an oxygen atom,        more preferably groups selected from benzyloxy, phenethyloxy,        and the like;    -   the “heteroaralkyl” group used either alone or in combination        with other radicals, is selected from groups containing an        heteroaryl radical, as defined above, attached directly to an        alkyl radicals, as define above, more preferably groups selected        from pyridinealkyl, thiophenealkyl, quinolinealkyl, and the        like;    -   the “alkenoxy” group used either alone or in combination with        other radicals, is selected from groups containing an alkenyl        radical, as defined above, attached to an oxygen atom, more        preferably selected from vinyloxy, allyloxy, butenoxy,        pentenoxy, hexenoxy, and the like;    -   the “haloalkyl” group is selected from an alkyl radical, as        defined above, suitably substituted with one or more halogens;        such as perhaloalkyl, more preferably, perfluoro(C₁-C₆)alkyl        such as fluoromethyl, difluoromethyl, trifluoromethyl,        fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo        substituted methyl, ethyl, propyl, butyl, pentyl or hexyl        groups;    -   the “haloalkoxy” group is selected from suitable haloalkyl, as        defined above, directly attached to an oxygen atom, more        preferably groups selected from fluoromethoxy, chloromethoxy,        fluoroethoxy, chloroethoxy and the like;    -   the “perhaloalkoxy” group is selected from a suitable        perhaloalkyl radical, as defined above, directly attached to an        oxygen atom, more preferably groups selected from        trifluoromethoxy, trifluoroethoxy, and the like;    -   the groups “heteroaryloxy”, “heteroaralkoxy”, “heterocycloxy”,        “heterocylylalkoxy” are selected from suitable heteroaryl,        heteroarylalkyl, heterocyclyl, heterocylylalkyl groups        respectively, as defined above, attached to an oxygen atom;    -   the “acyl” group used either alone or in combination with other        radicals, is selected from a radical containing one to eight        carbons, more preferably selected from formyl, acetyl,        propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl,        heptanoyl, benzoyl and the like, which may be substituted;    -   the “acyloxy” group used either alone or in combination with        other radicals, is selected from a suitable acyl group, as        defined above, directly attached to an oxygen atom, more        preferably such groups are selected from acetyloxy,        propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the        like;    -   the “acylamino” group used either alone or in combination with        other radicals, is selected from a suitable acyl group as        defined earlier, attached to an amino radical, more preferably        such groups are selected from CH₃CONH, C₂H₅CONH, C₃H₇CONH,        C₄H₉CONH, C₆H₅CONH and the like, which may be substituted;    -   the “mono-substituted amino” group used either alone or in        combination with other radicals, represents an amino group        substituted with one group selected from (C₁-C₆)alkyl,        substituted alkyl, aryl, substituted aryl or arylalkyl groups as        defined earlier, more preferably such groups are selected from        methylamine, ethylamine, n-propylamine, n-butylamine,        n-pentylamine and the like;    -   the “disubstituted amino” group used either alone or in        combination with other radicals, represents an amino group,        substituted with two radicals that may be same or different,        selected from (C₁-C₆)alkyl, substituted alkyl, aryl, substituted        aryl, or arylalkyl groups, as defined above, more preferably the        groups are selected from dimethylamino, methylethylamino,        diethylamino, phenylmethyl amino and the like;    -   the “arylamino” used either alone or in combination with other        radicals, represents an aryl group, as defined above, linked        through amino having a free valence bond from the nitrogen atom,        more preferably the groups are selected from phenylamino,        naphthylamine, N-methyl anilino and the like;    -   the “oxo” or “carbonyl” group used either alone (—C═O—) or in        combination with other radicals such as alkyl described above,        for e.g. “alkylcarbonyl”, denotes a carbonyl radical (—C═O—)        substituted with an alkyl radical described above such as acyl        or alkanoyl;    -   the “carboxylic acid” group, used alone or in combination with        other radicals, denotes a —COOH group, and includes derivatives        of carboxylic acid such as esters and amides;    -   the “ester” group used alone or in combination with other        radicals, denotes —COO— group, and includes carboxylic acid        derivatives, more preferably the ester moieties are selected        from alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,        and the like, which may optionally be substituted;        aryloxycarbonyl group such as phenoxycarboayl,        napthyloxycarbonyl, and the like, which may optionally be        substituted; aralkoxycarbonyl group such as benxyloxycarbonyl,        phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like,        which may optionally be substituted; heteroaryloxycarbonyl,        heteroaralkoxycarbonyl, wherein the heteroaryl group, is as        defined above, which may optionally be substituted;        heterocyclyloxycarbonyl, where the heterocyclic group, as        defined earlier, which may optionally be substituted;    -   the “amide” group used alone or is combination with other        radicals, represents an aminocarbonyl radical (H₂N—C═O), wherein        the amino group is mono- or di-substituted or unsubstituted,        more preferably the groups are selected from methyl amide,        dimethyl amide, ethyl amide, diethyl amide, and the like;    -   the “aminocarbonyl” group used either alone or in combination        with other radicals, may be selected from ‘aminocarbonyl’,        ‘aminocarbonylalkyl”, “n-alkylaminocarbonyl”,        “N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”,        “N-alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”,        and “N-alkyl-N-hydroxyaminocarbonylalkyl”, each of them being        optionally substituted. The terms “N-alkylaminocarbonyl” and        “N,N-dialkylaminocarbonyl” denotes aminocarbonyl radicals, as        defined above, which have been substituted with one alkyl        radical and with two alkyl radicals, respectively. Preferred are        “lower alkylaminocarbonyl” having lower alkyl radicals as        described above attached to aminocarbonyl radical. The terms        “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denote        amiocarbonyl radicals substituted, respectively, with one aryl        radical, or one alkyl, and one aryl radical. The term        “aminocarbonylalkyl” includes alkyl radicals substituted with        aminocarbonyl radicals;    -   the “hydroxyalkyl” group used either alone or in combination        with other radicals, is selected from an alkyl group, as defined        above, substituted with one or more hydroxy radicals, more        preferably the groups are selected from hydroxymethyl,        hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl,        hydroxyhexyl and the like;    -   the “aminoalkyl” group used alone or is combination with other        radicals, denotes an amino (—NH₂) moiety attached to an alkyl        radical, as defined above, which may be substituted, such as        mono- and di-substituted aminoalkyl. The term “alkylamino” used        herein, alone or in combination with other radicals, denotes an        alkyl radical, as defined above, attached to an amino group,        which may be substituted, such as mono- and di-substituted        alkylamino;    -   the “alkoxyalkyl” group used alone or in combination with other        radicals, denotes an alkoxy group, as defined above, attached to        an alkyl group as defined above, more preferably the groups may        be selected from methoxymethyl, ethoxymethyl, methoxyethyl,        ethoxyethyl and the like;    -   the “alkylthio” group used either alone or in combination with        other radicals, denotes a straight or branched or cyclic        monovalent substituent comprising an alkyl group as defined        above, linked through a divalent sulfur atom having a free        valence bond from the sulfur atom, more preferably the groups        may be selected from methylthio, ethylthio, propylthio,        butylthio, pentylthio and the like or cyclic alkylthio selected        from cyclopropylthio, cyclobutylthio, cyclopentylthio,        cyclohexylthio and the like, which may be optionally        substituted;    -   the “thioalkyl” group used either alone or in combination with        other radicals, denotes an alkyl group, as defined above,        attached to a group of formula —SR′, where R′ represents        hydrogen, alkyl or aryl group, e.g. thiomethyl,        methylthiomethyl, phenylthiomethyl and the like, which may be        optionally substituted.    -   the “alkoxycarbonylamino” group used alone or in combination        with other radicals, is selected from a suitable alkoxycarbonyol        group, as defined above, attached to an amino group, more        preferably methoxycarbonylamino, ethoxycarbonylamino, and the        like;    -   the “aminocarbonylamino”, “alkylaminocarbonylamino”,        “dialkylaminocarbonylamino” groups used alone or in combination        with other radicals, is a carbonylamino (—CONH₂) group, attached        to amino(NH₂), alkylamino group or dialkylamino group        respectively, where alkyl group is as defined above;    -   the “amidino” group used either alone or in combination with        other radicals, represents a —C(═NH)—NH₂ radical; the        “alkylamidino” group represents an alkyl radical, as described        above, attached to an amidino group;    -   the “alkoxyamino” group used either alone or in combination with        other radicals, represents a suitable alkoxy group as defined        above, attached to an amino group;    -   the “hydroxyamino” group used either alone or in combination        with other radicals, represents a —NHOH moiety, and may be        optionally substituted with suitable groups selected from those        described above;    -   the “sulfenyl” group or “sulfenyl derivatives” used alone or in        combination with other radicals, represents a bivalent group,        —SO— or R_(x)SO, where Rx is an optionally substituted alkyl,        aryl, heteroaryl, heterocyclyl, group selected from those        described above;    -   the “sulfonyl” group or “sulfones derivatives” used either alone        or in combination with other radicals, with other terms such as        alkylsulfonyl, represents a divalent radical —SO₂—, or        R_(x)SO₂—, where R_(x) is as defined above. More preferably, the        groups may be selected from “alkylsulfonyl” wherein suitable        alkyl radicals, selected from those defined above, is attached        to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl,        propylsulfonyl and the like, “arylsulfonyl” wherein an aryl        radical, as defined above, is attached to a sulfonyl radical,        such as phenylsulfonyl and the like.    -   the “sulfonyloxy” group used either alone or in combination with        other radicals, with other terms such as alkylsulfonyloxy,        represents a divalent radical —SO₃—, or R_(x)SO₃—, where R_(x)        is as defined above. More preferably, the groups may be selected        from “alkylsulfonyl” wherein suitable alkyl radicals, selected        from those defined above, is attached to a sulfonyloxy radical,        such as methanesulfonyloxy, ethanesulfonyloxy,        propanesulfonyloxy and the like, “arylsulfonyl” wherein an aryl        radical, as defined above, is attached to a sulfonyl radical,        such as benzenesulfonyloxy and the like

Suitable groups and substituents on the groups may be selected fromthose described anywhere in the specification.

Particularly useful compounds may be selected from

-   (S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid (1);-   Lithium    3-(4-((3-(4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoic    acid;-   3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)    yl)methyl)benzyl)oxy)phenyl)propanoic acid;-   Lithium    3-cyano-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)propanoic    acid;-   3-cyano-3-(4-((3-((2,2-dioxido-1H-thieno[3,4-c]pyrrol-5(3H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)propanoic    acid;-   3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoic    acid;-   (S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((1-(tert-butoxycarbonyl)-6,7-dihydro-1H-pyrrole[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((3,4-dihydroquinolin-1(2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   (S)-3-(4-((3-((2-Difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   Calcium(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   Calcium    (S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   (S)-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((1-Methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-(Indolin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid;-   (S)-3-(4-((3-((5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with formic acid;-   (S)-3-(4-((3-((4H-Thieno[2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   6-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-ium    formate;-   1-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-1,2,3,4-tetrahydroquinolin-1-ium    formate;-   (S)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(1H,4H,    6H)-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid;-   (S)-3-(4-((3-((2-hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-5-(3-((4-(1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic    acid;-   3-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoic    acid;-   (S)-3-(4-((3-((1-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)    benzyl)oxy)phenyl)hex-4-ynoic acid;-   (S)-3-(4-((3-((2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   Calcium(S)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   (S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-isopropylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (3S)-3-(4-((3-((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (3S)-3-(4-((3-((2-phenylpyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-(Pyrrolidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with formic acid;-   (S)-3-(4-((3-(Piperidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with formic acid;-   (S)-3-(4-((3-((1-isopropylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with formic acid;-   (R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((6,7-Dihydro-[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   3-(4-((3-((2-Methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   Calcium    (S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   (S)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-(pyrrolidine-1-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   Calcium    (S)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate;-   (S)-3-(4-((3-((2-Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with 2,2,2-trifluoroacetic acid;-   (S)-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with 2,2,2-trifluoroacetic acid;-   (S)-3-(4-((3-((7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with 2,2,2-trifluoroacetic acid;-   (S)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with 2,2,2-trifluoroacetic acid;-   (S)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid;-   (S)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid; and-   (S)-3-(4-((3-((2-((Methylamino)methyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic    acid compound with 2,2,2-trifluoroacetic acid;

The following compounds can be synthesized following the similarprocedure as described for example 1 with suitable modifications as arewell known to a person skilled in the art and are considered to beencompassed within the scope of the present invention.

3-(4-((3-((4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoicacid

3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoicacid

3-cyano-3-(4-((3-((2,2-dioxido-1H-thieno[3,4-c]pyrrol-5(3H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)propanoicacid

3-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoicacid

(S)-3-(4-((3-((2-methoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-(methylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((6,7-dihydrofuro[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-(2,2,2-trifluoroethyl)-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-isopropyl-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-(dimethylamino)-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-(tert-butyl)-6,7-dihyrdrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-oxo-1,2,6,7-tetrahydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(S)-3-(4-((3-((2-cyano-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(3S)-3-(4-((3-((4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

(3S)-3-(4-((3-((4-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

The novel compounds of this invention may be prepared using thereactions and techniques described in the below section along with,whenever appropriate other suitable processes known to a skilled person.The reactions are performed in solvents appropriate to the reagents andmaterials employed and are suitable for the transformations beingeffected. It is understood by those skilled in the art that the natureand order of the synthetic steps presented may be varied for the purposeof optimizing the formation of the compounds of the present inventionand also that certain steps may be modified, altered, obvious stepsadded or deleted in order to optimize as well as required for preparingthe compounds of the present invention. Such, obvious changes shouldalso be considered as being part of the present invention.

A compound of formula (I) can be prepared in accordance with reactionsas depicted in scheme 1.

The first step involves the reaction of substituted carboxylic acid(intermediate 1a) with an appropriate substituted heterocycle(intermediate 2a) under peptide bond formation conditions to giveintermediate 3a. The ester of intermediate 3a can be reduced using asuitable reducing agent such as diisobutylaluminum hydride, lithiumaluminum hydride or sodium borohydride etc. to give intermediate 4a.Intermediate 4a can be further reacted with compounds of formula IIunder Mitsunobu conditions to give intermediate 5a. Mitsunobu conditionsinvolve reacting an alcohol intermediate 4a with a nucleophile such as aphenol (formula II), using a suitable phosphine such as tributylphosphine, triphenyl phosphine, or triethyl phosphine and anazodicarbonyl such as ADDP or an azodicarboxylate (DEAD).

Alternatively, intermediate 4a can be converted to compound havingsuitable leaving group such as mesylate derivative (intermediate 6a)using an appropriate set of reactants and conditions such asmethanesulfonyl chloride and triethylamine.

The intermediate 6a can be reacted with compound of formula II usingdiisopropyl ethylamine or cesium carbonate to give intermediate 5a.

The intermediate 5a can be hydrolyzed to give carboxylic acid derivativeof formula (I) using bases such as lithium hydroxide, sodium hydroxideor potassium hydroxide.

In an optional step, a pharmaceutically acceptable salt of a compound offormula (I) can be formed by reaction of appropriate compound of formula(I) with a pharmaceutically acceptable base or with and acid in asuitable solvent under standard conditions. Optionally, the formation ofsuch salts can occur simultaneously upon hydrolysis of an esterintermediate.

The formation of such salts is well known and appreciated in the art.

The compounds of the present invention can be used either alone or incombination with one or more therapeutic agents selected from insulin,insulin derivatives and mimetics, insulin secretagogues, insulinsensitizers, biguanide agents, alpha-glucosidase inhibitors,insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1, GLP-1analogs, DPP-IV inhibitors, GPR-119 activators, sodium-dependent glucoseco-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone typePPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-loweringdrugs, rennin inhibitors, anti-thrombotic and anti-platelet agents andother anti-obesity agents or pharmaceutically acceptable salts thereof.Such use will depend on the condition of the patient being treated andis well within the scope of a skilled practitioner.

Following the general process described above, including suitablemodifications and additions which are within the scope of a skilledperson, the following compounds of formula (I) were prepared as follows:

1H NMR spectral data given in the examples (vide infra) are recordedusing a 400 MHz spectrometer (Bruker AVANCE-400) and reported in δscale. Until and otherwise mentioned the solvent used for NMR is CDCl₃.

Example 1(S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid (1)

Procedure i. Methyl3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate(intermediate 3)

To 3-(methoxycarbonyl)benzoic acid intermediate 1 (10 g, 55.5 mmol) wasadded thionyl chloride (16.21 mL, 222 mmol) in small portions at 25° C.followed by a drop of dimethylformamide. The reaction mixture wasstirred under refluxing for 3 h. Excess thionyl chloride was evaporatedunder reduced pressure at 100° C. The4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride intermediate 2(12.19 g, 69.4 mmol) was dissolved in 100 mL of water, to that addedsolution of sodium hydroxide (4.44 g, 111 mmol) in 25 mL of water. Freebase of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine was extracted indichloromethane (75 mL), dried over anhydrous potassium carbonate. Theacid chloride was dissolved in anhydrous dichloromethane (75 mL) andcooled to 0° C.

To the reaction mixture added drop wise triethylamine (15.47 mL, 111mmol) followed by solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine indichloromethane (75 mL) drop by drop at 0° C. The reaction mixture waswarmed to 25° C. and stirred it for 3 h. Progress of the reaction wasmonitored by TLC.

The reaction mixture was poured into ice-water (125 mL), adjusted pH ˜4with 10% HCl and extracted with dichloromethane (3×100 mL). The combinedorganic fractions were washed with 5% sodium hydroxide (100 ml) followedby brine (100 mL), dried over anhydrous Na₂SO₄ and evaporated on arotatory evaporator under reduced pressure to afford crude amideintermediate 3.

The crude product was purified by flash column chromatography using230-400 mesh silica-gel as a stationary phase and 10-50% ethylacetate-hexanes as a mobile phase afforded pure methyl3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoate (12 g,39.8 mmol, 71.7% yield)

ii. (3-((6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanol(intermediate 4)

To a solution of methyl3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)benzoateintermediate 3 (12 g, 39.8 mmol) in dry THF (100 mL) was added LiAlH₄(3.02 g, 80 mmol) in small portions at 25° C. The reaction mixture wasstirred under refluxing for 3 h. The progress of reaction was monitoredby TLC by using mobile phase 30% ethyl acetate in hexane. Suspension ofaqueous sodium sulfate was added drop wise to the reaction mixture toquench excess LiAlH₄. Ethyl acetate (150 mL) was added to the reactionmixture and refluxed for 30 min and decanted ethyl acetate, this processwas repeated three times to ensure no product in white slug of lithiumsulfate and aluminum hydroxide. The combined organic fractions weredried over anhydrous Na₂SO₄ and evaporated on a rotatory evaporatorunder reduced pressure to afford crude product as pale yellow stickymass of intermediate 4.

The crude alcohol intermediate 4 was purified by flash columnchromatography using 230-400 mesh silica-gel as stationary phase and10-50% ethyl acetate-hexane as a mobile phase afforded pure(3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanolintermediate 4 (5.41 g, 20.86 mmol, 52.4% yield).

iii.(S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid (1)

To a solution of(3-((6-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)methanolintermediate 4 (0.16 g, 0.617 mmol) in 5 mL of anhydrous tetrahydrofuranwas added triethylamine (0.258 ml, 1.851 mmol) followed bymethanesulfonyl chloride (141 mg, 1.234 mmol) at 0° C. The reactionmixture was stirred at 25° C. for 1 h. The progress of the reaction wasmonitored by TLC. The reaction mixture was poured into ice-water (25 mL)and extracted with dichloromethane (3×25 mL). The combined organicfractions were dried over anhydrous Na₂SO₄ and evaporated on a rotatoryevaporator under reduced pressure to afford3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl mesylateintermediate (5) as pale yellow sticky mass.

To a solution of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate intermediate6 (162 mg, 0.740 mmol) in Acetonitrile (5.00 ml) was added cesiumcarbonate (603 mg, 1.851 mmol) followed by solution of3-((6,7-dihydrothieno[3,2c]pyridin-5(4H)-yl)methyl)benzyl mesylate 5 in2 mL of acetonitrile at 25° C. Reaction mixture was stirred for 3 h at75° C. Progress of the reaction was monitored by TLC. After completionof the reaction, volatiles were evaporated off under reduced pressure.The reaction mixture was poured into ice-water (25 mL) and product wasextracted with dichloromethane (3×25 mL). The combined organic fractionswere dried over anhydrous Na₂SO₄ and evaporated on a rotatory evaporatorunder reduced pressure to afford crude product as pale yellow stickymass. Ethereal hydrochloride solution was added to the crude product,ether was evaporated off and residue was triturated with ethyl acetateafforded 65 mg of (S)-methyl3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoatehydrochloride intermediate (7). Ester hydrochloride salt intermediate 7(60 mg, 0.121 mmol) was hydrolyzed using mixture of THF (2 mL) and MeOH(1 mL) was added NaOH (24.19 mg, 0.605 mmol) in water (1 mL) at 25° C.Reaction mixture was stirred for 12 h at 25° C. Progress of the reactionwas monitored by TLC. After completion of the reaction, volatiles wereevaporated off, the residue was treated with ice-water (5 mL), adjustedpH ˜4 (1N HCl), exacted with dichloromethane (3×25 mL) and dried overanhydrous Na₂SO₄. Evaporation of solvents on a rotatory evaporator underreduced pressure to afford crude product. Crude acid was purified bypreparative TLC to afford(S)-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid 1 (42 mg, 0.094 mmol, 78% yield)

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.42 (s, 1H), 7.37-7.24 (m, 6H), 6.94 (d,J=8.4 Hz, 2H), 6.75 (d, J=5.2 Hz, 1H), 5.07 (s, 2H), 3.94 (m, 1H), 3.68(s, 2H), 3.43 (s, 2H), 2.78-2.72 (m, 4H), 2.57-2.55 (m, 2H), 1.77 (d,J=1.6 Hz, 3H); ESIMS: 446.2 (M+H)⁺.

The following compounds can be prepared by following the general scheme1 and the process described in Example 1 above, including their suitablemodifications well within the scope of a skilled person.

Example 2 Lithium3-(4-((3-((4H-furo[3,4-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)-3-cyanopropanoicacid

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.44 (s, 1H), 7.35-7.28 (m, 7H), 6.98 (d,J=8.8 Hz, 2H), 6.09 (s, 2H), 4.27 (dd, J=6.4, 8.4 Hz, 1H), 3.86 (s, 2H),3.57 (s, 4H), 2.53-2.41 (m, 1H), 2.33-2.32 (m, 1H)

Example 3 3-cyano-3-(4-((3-((4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)methyl)benzyl)oxy)phenyl)propanoic acid

¹H NMR: (CDCl₃, 400 MHz): −7.47 (d, J=5.2 Hz, 1H), 7.37-7.23 (m, 6H),7.11 (d, J=5.2 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 5.06 (s, 2H), 4.77-4.68(m, 2H), 4.19 (t, J=7.6 Hz, 1H), 3.55 (t, J=6.8 Hz, 2H), 3.06-2.98 (m,3H), 2.88-2.82 (m, 1H)

Example 4 Lithium3-cyano-3-(4-((3-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)propanoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 7.48 (s, 1H), 7.39-7.36 (m, 3H), 7.31 (dd,J=2, 6.8 Hz, 2H), 6.98 (dd, J=2.4, 6.8 Hz, 2H), 5.10 (s, 2H), 4.30-4.26(m, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.89 (s, 2H), 3.83 (s, 2H), 2.97 (t,J=5.6 Hz, 2H), 2.74 (dd, J=8.8, 15.6 Hz, 1H), 2.58 (dd, J=8.8, 15.6 Hz,1H).

Example 53-cyano-3-(4-((3-((2,2-dioxido-1H-thieno[3,4-c]pyrrol-5(3H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)propanoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 7.66 (d, 1H), 7.60-7.51 (m, 3H), 7.35 (dd,J=2, 6.8 Hz, 2H), 7.03 (dd, J=2, 6.4 Hz, 2H), 5.17 (s, 2H), 4.60 (s,2H), 4.35-4.31 (m, 1H), 4.28 (s, 4H), 3.94 (s, 4H), 2.99 (dd, J=8.4,16.8 Hz, 1H), 2.85 (dd, J=6.4, 16.4 Hz, 1H).

Example 63-cyano-3-(4-((3-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.58 (s, 1H), 7.37-7.32 (m, 2H), 7.22-7.16(m, 4H), 6.88 (dd, J=2, 6.8 Hz, 2H), 6.71 (d, J=5.2 Hz, 1H), 5.00 (s,2H), 4.18-4.14 (m, 1H), 3.99 (s, 2H), 3.88 (s, 2H), 3.19-3.16 (m, 2H),3.03-3.00 (m, 2H), 2.87-2.81 (m, 1H), 2.70-2.64 (m, 1H).

Example 7(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.38-7.25 (m, 6H), 6.88 (d, J=5.2 Hz, 2H),6.33 (s, 1H), 5.04-4.98 (m, 2H), 4.05-4.00 (m, 1H), 3.80-3.71 (m, 2H),3.64-3.55 (m, 2H), 2.92-2.61 (m, 6H), 2.39 (s, 3H), 1.82 (d, J=2.4 Hz,3H).

Example 8(S)-3-(4-((3-((1-(tert-butoxycarbonyl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.47-7.38 (m, 4H), 7.27 (d, J=8.8 Hz, 2H),7.18 (d, J=3.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 5.94 (d, J=3.2 Hz, 2H),5.05 (s, 2H), 4.08 (s, 2H), 4.05-4.01 (m, 1H), 3.85 (s_((br)), 2H),3.30-3.15 (m, 4H), 2.78 (dd, J=8.8, 15.2 Hz, 1H), 2.65 (dd, J=8, 15.2Hz, 1H), 1.80 (d, J=2.4 Hz, 3H), 1.59 (s, 9H).

Example 9(S)-3-(4-((3-((6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 8.51 (s, 1H), 7.42-7.33 (m, 4H), 7.25 (d,J=8.9 Hz, 2H), 6.81 (d, J=9 Hz, 2H), 6.63 (t, J=2.4 Hz, 1H), 5.89 (t,J=2.4 Hz, 1H), 5.06 (s, 2H), 4.07-3.99 (m, 3H), 3.87 (s, 2H), 3.08(s_((br)), 2H), 2.80-2.74 (m, 3H), 2.61 (m, 1H), 1.80 (d, J=2.4 Hz, 3H)

Example 10(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.41-7.38 (m, 4H), 7.27 (d, J=8.4 Hz, 2H),6.85 (d, J=8.4 Hz, 2H), 5.19-5.08 (m, 2H), 4.04-3.91 (m, 1H), 3.75(s_((br)), 4H), 2.87-2.69 (m, 4H), 2.66 (s, 3H), 2.58-2.41 (m, 2H), 1.80(d, J=2.4 Hz, 3H)

Example 11(S)-3-(4-((3-((3-(trifluoromethyl)-6,7-dihydrothiazolo[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.40-7.26 (m, 6H), 6.86 (d, J=8.8 Hz, 2H),5.12 (dd, J=12.8, 18.4 Hz, 2H), 4.15-4.12 (m, 2H), 4.04-3.99 (m, 1H),3.86-3.69 (m, 4H), 3.00-2.85 (m, 2H), 2.82 (dd, J=6.8, 15.2 Hz, 1H),2.65 (dd, J=6.8, 15.2 Hz, 1H), 1.82 (J=2 Hz, 3H).

Example 12(S)-3-(4-((3-(isoindolin-2-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acidtrifluoroacetic acid

¹H NMR (CDCl₃, 400 MHz) δ: 7.52-7.44 (m, 2H), 7.42-7.34 (m, 4H),7.31-7.26 (m, 4H), 6.85 (d, J=8.4 Hz, 2H), 5.09 (s, 2H), 4.70 (s, 2H),4.34-4.29 (m, 2H), 4.04-4.00 (m, 1H), 3.32 (s, 2H), 2.85-2.78 (m, 1H),2.70-2.63 (m, 1H), 1.80 (d, J=2.4 Hz, 3H).

Example 13(S)-3-(4-((3-((3,4-dihydroquinolin-1(2H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.32-7.22 (m, 6H), 6.99-6.90 (m, 4H),6.60-6.57 (m, 1H), 6.50 (d, J=8.4 Hz, 2H), 5.02 (s, 2H), 4.49 (s, 2H),4.49 (s_((br)), 1H), 3.36 (s_((br)), 2H), 3.02-2.87 (m, 4H), 2.02-2.00(m, 2H), 1.80 (s, 3H).

Example 14(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.36 (m, 3H), 7.32-7.25 (m, 3H), 6.90(d, J=8.4 Hz, 2H), 6.66 (s, 2H), 4.06-4.02 (m, 1H), 3.94-3.92 (m, 2H),3.68 (s_((br)), 2H), 3.01 (s_((br)), 2H), 2.88-2.85 (m, 2H), 2.80-2.74(m, 1H), 2.69-2.63 (m, 1H), 1.83 (d, J=2.4 Hz, 3H).

Example 15(S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.47 (s, 1H), 7.42-7.27 (m, 5H), 7.22-7.15(m, 3H) (m, 3H), 7.05-7.02 (m, 1H), 6.93 (d, J=8.8 Hz, 2H), 5.10-5.03(m, 2H), (m, 2H), 4.10-4.06 (m, 1H), 2.02-2.00 (m, 2H), 1.80 (s, 3H),3.87-3.80 (m, 4H), 2.96-2.86 (m, 4H), 2.86-2.80 (m, 1H), 2.78-2.74 (m,1H), 1.86 (d, J=2.4 Hz, 3H).

Example 16calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.40 (s, 1H), 7.35-7.23 (m, 5H), 6.88 (d,J=8.4 Hz, 2H), 6.41 (s, 1H), 5.04 (s, 2H), 4.00 (s_((br)), 1H), 3.64 (s,2H), 3.32 (s, 2H), 2.68 (s, 4H), 2.40-2.37 (m, 1H), 2.33 (s, 3H),2.27-2.21 (m, 1H), 1.74 (d, J=2 Hz, 3H).

Example 17calcium(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate(S)-3-(4-((3-((2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.41 (s, 1H), 7.34-7.23 (m, 5H), 6.89 (d,J=8.8 Hz, 2H), 5.01 (s, 2H), 4.05-3.99 (m, 1H), 3.68 (s, 2H), 3.56 (s,2H), 2.76-2.74 (m, 2H), 2.68 (s_((br)), 2H), 2.56 (s, 3H), 2.40-2.36 (m,1H), 2.26-2.22 (m, 1H), 1.73 (d, J=2.4 Hz, 3H).

Example 18(S)-3-(4-((3-((2-Difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.39-7.26 (m, 6H), 6.91-6.59 (m, 4H), 5.03(s, 2H), 4.12-4.10 (m, 1H), 3.73 (s, 2H), 3.55 (s, 2H), 2.88-2.64 (m,6H), 1.82 (d, J=2.4 Hz, 3H).

Example 19Calcium(S)-3-(4-((3-((2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.41 (s, 1H), 7.37-7.24 (m, 5H), 6.93-6.89(m, 3H), 5.06 (s, 2H), 3.96-3.94 (m, 1H), 3.66 (s, 2H), 3.38 (s, 2H),2.71 (s, 4H), 2.49-2.32 (m, 2H), 1.76 (d, J=2.4 Hz, 3H).

Example 20Calcium(S)-3-(4-((3-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.37 (s, 1H), 7.35-7.23 (m, 5H), 7.11-7.07(m, 3H), 6.98-6.97 (m, 1H), 6.89 (d, J=8.8 Hz, 2H), 5.05 (s, 2H),3.99-3.97 (m, 1H), 3.64 (s, 2H), 3.52 (s, 2H), 2.79-2.77 (m, 2H),2.65-2.64 (m, 2H), 2.42-2.36 (m, 1H), 2.28-2.22 (m, 1H), 1.74 (d, J=2.4Hz, 3H).

Example 21(S)-3-(4-((3-((7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 8.94 (s, 1H), 8.30 (s, 1H), 7.45 (s, 1H),7.38-7.25 (m, 5H), 6.86 (d, J=2, 6.8 Hz, 2H), 5.15-5.09 (m, 2H),4.06-4.03 (m, 1H), 3.78-3.62 (m, 4H), 2.89-2.73 (m, 6H), 1.82 (d, J=2.4Hz, 3H).

Example 22(S)-3-(4-((3-((1-Methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.43-7.24 (m, 6H), 7.17 (s, 1H), 6.88 (td,J=5.2, 8.4 Hz, 2H), 5.03 (s, 2H), 4.07 (s, 2H), 4.02-3.97 (m, 5H), 3.75(s, 3H), 2.78-2.72 (m, 1H), 2.66-2.60 (m, 1H), 1.80 (d, J=2.4 Hz, 3H).

Example 23(3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.53-7.25 (m, 6H), 6.89 (d, J=8.4 Hz, 2H),5.09 (s, 2H), 4.54-4.52 (m, 2H), 4.05-3.93 (m, 3H), 3.24-2.94 (m, 4H),2.81-2.75 (m, 1H), 2.69-2.63 (m, 1H), 2.42 (d, J=8.8 Hz, 2H), 1.83 (d,J=2.4 Hz, 3H).

Example 24(S)-3-(4-((3-(Indolin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid

¹H NMR (CDCl₃, 400 MHz) δ: 7.41 (s, 1H), 7.37-7.25 (m, 5H), 7.10-7.05(m, 2H), 6.93-6.89 (m, 2H), 6.70-6.66 (m, 1H), 6.51 (d, J=7.6 Hz, 1H),5.03 (s, 2H), 4.26 (s, 2H), 4.07-4.02 (m, 1H), 3.30 (t, J=8.4 Hz, 2H),2.96 (t, J=8.4 Hz, 2H), 2.83-2.76 (m, 1H), 2.73-2.67 (m, 1H), 1.83 (d,J=2.4 Hz, 3H).

Example 25(S)-3-(4-((3-((5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 8.50 (s, 1H), 7.49 (s, 1H), 7.40-7.35 (m,3H), 7.28 (d, J=6.8 Hz, 2H), 6.93 (d, J=6.8 Hz, 2H), 5.01 (s, 2H),4.15-4.11 (m, 2H), 4.00-3.97 (m, 1H), 3.87-3.83 (m, 4H), 2.97-2.94 (m,2H), 2.66-2.62 (m, 2H), 1.81 (d, J=2.4 Hz, 3H).

Example 26(S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.52-7.20 (m, 6H), 6.81 (d, J=8.8 Hz, 2H),5.21-5.12 (m, 2H), 4.00-3.95 (m, 1H), 3.78-3.67 (m, 2H), 3.23-2.59 (m,8H), 2.04-1.97 (m, 1H), 1.81 (d, J=2.4 Hz, 3H), 1.00-0.96 (m, 4H).

Example 27(3S)-3-(4-((3-((5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid compound with formic acid

¹H NMR (CDCl₃, 400 MHz) δ: 8.45 (s_((br)), 0.78H, HCOOH), 7.52-7.15 (m,9H), 7.16 (d, J=7.2 Hz, 1H), 6.78 (dd, J=2.8, 11.6 Hz, 2H), 5.12 (s,2H), 4.05-4.00 (m, 1H), 3.93-3.68 (m, 4H), 3.04-3.01 (m, 2H), 2.83-2.78(m, 3H), 2.68-2.64 (m, 1H), 2.58-2.40 (m, 6H), 1.77 (d, J=2.4 Hz, 3H).

Example 28(S)-3-(4-((3-((4H-Thieno[2,3-c]pyrrol-5(6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.43 (s, 1H), 7.39-7.24 (m, 6H), 6.86 (d,J=8.4 Hz, 2H), 6.80 (d, J=5.2 Hz, 1H), 5.06-4.99 (m, 2H), 4.17-4.00 (m,7H), 2.77-2.71 (m, 1H), 2.65-2.59 (m, 1H), 1.80 (d, J=2.4 Hz, 3H).

Example 296-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-iumformate

¹H NMR (CDCl₃, 400 MHz) δ: 8.98 (s, 1H), 8.63 (s, 1H), 8.37 (s, 1H),7.45 (s, 1H), 7.37-7.31 (m, 3H), 7.25 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 5.08 (s, 2H), 3.95-3.90 (m, 7H), 2.55-2.52 (m, 1H), 2.12 (s,3H).

Example 301-(3-((4-((S)-1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-7-methoxy-1,2,3,4-tetrahydroquinolin-1-iumformate

¹H NMR (CDCl₃, 400 MHz) δ 8.21 (s), 0.28 (formate), 7.33-7.28 (m, 3H),7.25 (d, J=8.8 Hz, 2H), 7.19 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H),6.55 (d, J=2.8 Hz, 1H), 6.51-6.48 (dd, J=8.8 Hz & 2.8 Hz, 1H), 6.39 (d,J=8.8 Hz, 1H), 5.0 (s, 2H), 4.39 (s, 2H), 3.95-3.90 (m, 3H), 3.60 (m,4H), 3.24 (t, 3H), 2.70 (m, 2H), 2.58 (d, 2H), 2.06 (t, 2), 1.07-1.08(s, 3H).

Example 31(S)-3-(4-((3-((2-Chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.41-7.30 (m, 3H), 7.35-7.27 (m, 3H), 6.90(d, J=8.4 Hz, 2H), 5.07 (s, 1H), 4.07-4.02 (m, 1H), 3.82 (s, 2H), 3.72(s, 2H), 2.98-2.95 (m, 2H), 2.86-2.68 (m, 5H), 1.83 (d, J=2.4 Hz, 3H).

Example 32(S)-3-(4-((3-((2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.39-7.35 (m, 3H), 7.29-7.26 (m, 3H), 6.90(d, J=8.4 Hz, 2H), 5.05 (s, 2H), 4.06-4.01 (m, 1H), 3.79 (s, 2H), 3.70(s, 2H), 2.92-2.66 (m, 6H), 1.82 (d, J=2.4 Hz, 3H).

Example 33 (S)-3-(4-((3-(pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acid

¹H NMR (CDCl₃, 400 MHz): −δ7.32-7.53 (m, 3H), 7.19-7.29 (m, 4H),6.82-6.84 (m, 2H), 5.16 (s, 2H), 3.90-4.06 (m, 5H), 3.57 (s, 2H),2.80-2.85 (m, 1H), 1.81 (s, 3H);

Example 34(S)-3-(4-((3-((2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO, 400 MHz): −δ 7.38 (s, 1H), 7.23-7.33 (m, 5H), 6.92 (d,J=8.8 Hz, 2H), 6.56 (s, 1H), 5.35 (s, 2H), 3.91-3.94 (m, 1H), 3.72-3.84(m, 4H), 3.40-3.50 (m, 2H (merger), 2.86-2.94 (m, 2H), 2.73-2.76 (m,2H), 2.50-2.58 (m, 2H), 1.76 (s, 3H);

Example 35(S)-5-(3-((4-(1-carboxypent-3-yn-2-yl)phenoxy)methyl)benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid

¹H NMR (DMSO-d₆, 400 MHz): −7.42 (s, 1H), 7.34-7.31 (m, 2H), 7.27-7.26(m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J=8.8 Hz, 2H),5.09 (s, 2H), 3.95-3.91 (m, 1H), 3.65 (s, 2H), 3.29 (s, 2H), 2.74-2.71(m, 4H), 2.63-2.52 (m, 2H), 1.76 (s, 3H).

Example 363-cyclopropyl-3-(3-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)propanoicacid

¹H NMR (DMSO-d₆, 400 MHz): −7.46 (s, 1H), 7.37-7.31 (m, 3H), 7.14 (t,J=8 Hz, 2H), 6.81-6.79 (m, 2H), 6.44 (s, 1H), 5.05 (s, 2H), 3.78 (s,2H), 3.32 (s, 2H), 2.82-2.74 (m, 4H), 2.49-2.44 (m, 2H), 2.36-2.34 (m,4H), 1.30-1.28 (m, 1H), 0.49-0.47 (m, 1H), 0.27-0.24 (m, 2H),0.004-0.002 (m, 1H).

Example 37(S)-3-(4-((3-((1-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

¹H NMR (CDCl₃, 400 MHz): δ 7.53 (s, 1H), 7.47-7.32 (d, 3H), 7.24-7.12(m, 2H), 6.85 (d, 2H), 6.51 (d, 1H), 5.58 (d, 1H), 5.0-4.95 (d, 2H),3.9-4.1 (m, 1H), 3.87 (d, 1H), 3.80 (d, 1H), 3.48 (s, 3H), 2.9-3.1 (m,3H), 1.08 (m, 3H).

Example 38(S)-3-(4-((3-((2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): δ 8.23 (s, 1H), 7.40 (s, 1H), 7.35 (d, 2H),7.32-7.24 (m, 3H), 6.93 (d, J=8.4 Hz, 2H), 6.68 (s, 2H), 5.06 (s, 2H),3.9-4.0 (m, 1H), 3.35 (s, 3H), 2.70-2.66 (m, 2H), 2.58 (d, 2H), 2.44 (d,3H).

Example 39 Calcium(S)-3-(4-((3-((2-chloro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (CDCl₃, 400 MHz) δ: 7.39 (s, 1H), 7.36-7.23 (m, 5H), 6.88 (d,J=8.8 2H), 6.78 (s, 1H), 5.04 (s, 2H), 3.99 (s_((br)), 1H), 3.65 (s,2H), 3.34 (s, 2H), 2.70 (s_((br)), 4H), 2.37-2.31 (m, 1H), 2.25-2.19 (m,1H), 1.73 (d, J=2.4 Hz, 3H).

Example 40(S)-3-(4-((3-((2-carbamoyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −12.22 (br s, 1H), 7.76 (br s, 1H), 7.42 (s,1H), 7.37-7.25 (m, 7H), 6.94 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 3.95-3.91(m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.78-2.76 (m, 2H), 2.72-2.70 (m,2H), 2.60-2.57 (m, 2H), 1.77 (s, 3H).

((S)-3-(4-((3-((2-isopropylpyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO, 400 MHz): δ 12.25 (m, 2H), 7.48-7.51 (m, 2H), 7.39 (s,3H), 7.27 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.09 (s, 2H),4.40-4.47 (m, 1H), 4.10-4.20 (m, 2H), 3.70-3.90 (m, 4H), 2.66-2.66 (m,2H), 1.77 (s, 3H), 1.36-138 (m, 6H).

Example 42(S)-3-(4-((3-((2-(methoxycarbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −12.22 (br s, 1H), 7.50 (s, 1H), 7.41 (s,1H), 7.37-7.24 (m, 5H), 6.92 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 3.95-3.91(m, 1H), 3.77 (s, 3H), 3.68 (s, 2H), 3.46 (s, 2H), 2.84-2.81 (m, 2H),2.74-2.70 (m, 2H), 2.58-2.53 (m, 2H), 1.90 (s, 3H).

Example 43(S)-3-(4-((3-((2-cyano-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO, 400 MHz): δ 8.83 (s, 1H), 7.24-7.41 (m, 6H), 6.92-6.94 (m,2H), 5.09 (s, 2H), 3.91-3.94 (m, 1H), 3.73 (s, 2H), 3.45 (s, 2H),2.86-2.94 (m, 2H), 2.73-2.76 (m, 2H), 2.50-2.58 (m, 2H), 1.76 (s, 3H);

Example 44(S)-3-(4-((3-((2-formyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −9.79 (s, 1H), 7.70 (s, 1H), 7.42 (s, 1H),7.36-7.31 (m, 3H), 7.26-7.24 (d, J=8 Hz, 2H), 6.94-6.92 (d, J=8 Hz, 2H),5.07 (s, 2H), 3.93 (br s, 1H), 3.70 (s, 2H), 3.50 (s, 2H), 2.89 (s, 2H),2.74 (s, 2H), 1.76 (s, 3H), 1.23 (s, 2H).

(S)-3-(4-((3-((2-methyl-6,7-dihydrothieno[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): δ 7.41 (s, 1H), 7.35 (d, J=6.4 Hz, 2H), 7.30(m, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.73 (s, 1H),5.07 (s, 2H), 3.96-3.92 (m, 3H), 3.68 (s, 2H), 3.52 (s, 2H), 2.84 (t,2H), 2.66 (t, 2H), 2.08 (s, 3H), 1.77 (s, 3H)

Example 46(S)-3-(4-((3-((2-(methylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −7.42 (s, 1H), 7.35-7.24 (m, 6H),7.1-6.93-6.91 (m, 2H), 5.07 (s, 2H), 3.9 (m, 1H), 3.68 (s, 2H), 3.41 (s,2H), 2.71-2.70 (m, 2H), 2.67-2.66 (m, 6H), 1.76 (s, 3H).

Example 47(S)-3-(4-((3-((2-(dimethylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −7.53 (s, 1H), 7.40-7.22 (m, 4H), 7.1-6.68(m, 3H), 5.08 (s, 2H), 4.12-4.03 (m, 1H), 3.78-3.71 (m, 2H), 3.50 (s,2H), 3.17 (s, 6H), 2.95-2.88 (m, 2H), 2.83-2.63 (m, 2H), 1.83 (s, 3H).

Example 48(3S)-3-(4-((3-((2-Methyl-5-(4-(methylsulfonyl)phenyl)pyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.93-7.90 (m, 2H), 7.82-7.76 (m, 2H),7.53-7.16 (m, 7H), 6.92-6.86 (m, 3H), 5.11-5.01 (m, 3H), 4.45-4.30 (m,1H), 4.07-3.98 (m, 3H), 3.30-3.20 (m, 1H), 3.097-3.090 (m, 3H), 3.03 (s,1H), 2.87-2.68 (m, 4H), 2.33-1.98 (m, 8H), 1.84-1.82 (m, 5H), 1.62-1.60(m, 4H)

Example 49(S)-3-(4-((3-((2-(Methylsulfonyl)-7,8-dihydrothieno[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 8.48 (s, 1H), 7.43-7.27 (m, 6H), 6.91 (dd,J=8.8, 2 Hz, 2H), 5.07 (s, 2H), 4.07-4.03 (m, 1H), 3.80 (s, 2H), 3.72(s, 2H), 3.32 (s, 3H), 3.15-3.09 (m, 2H), 2.92-2.89 (m, 2H), 2.84-2.78(m, 1H), 2.74-2.68 (m, 1H) 1.83 (d, J=2.4 Hz, 3H)

Example 50(S)-3-(4-((3-((2-Methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 8.09 (s, 1H), 7.53-7.26 (m, 6H), 6.87 (dd,J=6.8, 2 Hz, 2H), 5.17-5.08 (m, 2H), 4.07-4.02 (m, 1H), 3.98 (s, 3H),3.75 (s_((br)), 2H), 3.58 (s_((br)), 2H), 2.88-2.63 (m, 6H), 1.82 (d,J=2.4 Hz, 3H)

Example 51(3S)-3-(4-((3-((2-phenylpyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz): δ 7.43-7.45 (m, 2H), 7.21-7.35 (m, 9H),6.89-6.91 (d, J=8 Hz, 2H), 5.0 (s, 2H), 4.03 (m, 1H), 3.81-3.85 (m, 1H),3.37-3.41 (m, 1H), 3.11-3.17 (m, 3H), 2.74-2.80 (m, 1H), 2.64-2.69 (m,1H), 3.37-2.14-2.51 (m, 2H), 1.85-1.92 (m, 1H), 1.81 (s, 3H), 1.71-1.75(m, 2H);

Example 52(S)-3-(4-((3-(Pyrrolidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acidcompound with formic acid

¹H NMR (CD₃OD, 400 MHz) δ: 8.51 (s, 1H, HCOOH), 7.60 (s, 1H), 7.55-7.45(m, 3H), 7.28 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.14 (s, 2H),4.34 (s, 2H), 4.02-3.98 (m, 1H), 3.27-3.24 (m, 4H), 2.62-2.50 (m, 2H),2.08-2.04 (m, 4H), 1.80 (d, J=2.4 Hz, 3H)

Example 53(S)-3-(4-((3-(Piperidin-1-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoic acidcompound with formic acid

¹H NMR (CD₃OD, 400 MHz) δ: 8.50 (s, 1H, HCOOH), 7.58-7.43 (m, 4H), 7.29(d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.15 (s, 2H), 4.23 (s, 2H),4.09-4.03 (m, 1H), 3.12-3.08 (m, 4H) 2.63-2.49 (m, 2H), 1.83-1.79 (m,7H), 1.64-1.61 (m, 2H)

Example 54(S)-3-(4-((3-((1-isopropylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid compound with formic acid

¹H NMR (CD₃OD, 400 MHz) δ: 8.41 (s, 1H, HCOOH), 7.54 (s, 1H), 7.43-7.40(m, 3H), 7.29 (dd, J=7.2, 2 Hz, 2H), 7.21 (s, 1H), 6.93 (dd, J=6.8, 2Hz, 2H), 5.11 (s, 2H), 4.45-4.41 (m, 1H), 4.14 (s, 2H), 4.07 (s, 2H),4.02-3.95 (m, 1H), 3.88 (s, 2H), 2.63-2.59 (m, 2H), 1.80 (d, J=2.4 Hz,3H), 1.42 (d, J=6.8 Hz, 6H).

Example 55(R)-3-(4-((3-((2-methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 8.31 (s, 0.36H, Residual HCOOH), 7.47-7.25(m, 6H), 6.86 (td, J=9.6, 2.8 Hz, 2H), 6.34 (s, 1H), 5.04 (s, 2H),4.07-4.01 (m, 3H), 3.8 (s_((br)), 2H), 3.20-3.12 (m, 2H), 2.97-2.95 (m,2H), 2.78-2.73 (m, 1H), 2.66-2.61 (m, 1H), 2.41 (s, 3H), 1.80 (d, J=2.4Hz, 3H).

Example 56(R)-3-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 8.15 (s, 0.3H, Residual HCOOH), 7.41-7.27 (m,6H), 6.88 (d, J=8.4 Hz, 2H), 5.15-5.07 (m, 2H), 4.06-4.02 (m, 1H),3.90-3.82 (m, 4H), 2.96-2.92 (m, 2H), 2.88-2.64 (m, 7H), 1.82 (d, J=2.4Hz, 3H)

Example 57(S)-3-(4-((3-((6,7-Dihydro-[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 7.59-7.58 (m, 2H), 7.58-7.43 (m, 3H), 7.29(d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.14 (s, 2H), 4.58-4.55 (m,2H), 4.19 (s, 2H), 4.15 (s, 2H), 4.01-3.97 (m, 1H), 3.44-3.41 (m, 2H),2.70-2.58 (m, 2H), 1.81 (d, J=2.4 Hz, 3H).

Example 583-(4-((3-((2-Methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-4.27 (m, 5H), 6.87 (dd, J=11.2, 3 Hz,2H), 6.34 (s, 1H), 5.05 (s, 2H), 4.06-4.02 (m, 2H), 3.98 (s, 2H), 3.74(s, 2H), 3.10-3.04 (m, 2H), 2.92-2.89 (m, 2H), 2.79-2.73 (m, 1H),2.67-2.61 (m, 1H), 2.41 (s, 3H), 1.81 (d, J=2.4 Hz, 3H).

Example 593-(4-((3-((2-Methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.35 (m, 4H), 7.29-7.27 (m, 2H), 6.88(d, J=8.8 Hz, 2H), 5.14-5.07 (m, 2H), 4.06-4.03 (m, 1H), 3.93-3.85 (m,4H), 2.99-2.97 (m, 2H), 2.86-2.64 (m, 7H), 1.82 (d, J=2.4 Hz, 3H

Example 60 Calcium(S)-3-(4-((3-((2-chloro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.39 (s, 1H), 7.36-7.23 (M, 5H), 6.88 (d,J=8.8 Hz, 2H), 5.03 (s, 2H), 4.02-3.09 (m, 1H), 3.69 (s, 2H), 3.39 (s,2H), 2.80-2.77 (m, 2H), 2.72-2.69 (m, 2H), 2.41-2.36 (m, 1H), 2.27-221(m, 1H), 1.73 (d, J=2.4 Hz, 3H).

Example 61(S)-3-(4-((3-((2-(cyclopropylcarbamoyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −8.34 (br s, 1H), 7.41 (s, 1H), 7.36-7.29 (m,3H), 7.27-7.24 (m, 3H), 6.67 (d, J=8.4 Hz, 2H), 5.07 (s, 2H), 3.95-3.91(m, 1H), 3.67 (s, 2H), 3.42 (s, 2H), 2.77-2.66 (m, 5H), 2.57-2.51 (m,2H), 1.76 (s, 3H), 0.67-0.62 (m, 2H), 0.53-0.49 (m, 2H

Example 62(S)-3-(4-((3-((2-(pyrrolidine-1-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (DMSO-d₆, 400 MHz): −7.42 (s, 1H), 7.37-7.26 (m, 3H), 7.25-7.13(m, 3H), 6.93 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 3.94-3.87 (m, 1H), 3.68(br s, 4H), 3.43 (br s, 4H), 2.80-2.73 (m, 4H), 2.59-2.50 (m, 2H),2.91-1.81 (m, 4H), 1.76 (s, 3H)

Example 63(S)-3-(4-((3-((2-Aacetamido-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 7.56 (s, 2H), 7.50-7.41 (m, 3H), 7.28 (d,J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.35 (s, 1H), 5.12 (s, 2H), 4.15(s, 2H), 4.01-3.97 (m, 1H), 3.84 (s, 2H), 3.25-3.22 (m, 2H), 2.96-2.93(m, 2H), 2.66-2.52 (m, 2H), 2.10 (s, 3H), 1.79 (d, J=2.4 Hz, 3H).

Example 64 Calcium(S)-3-(4-((3-((2-cyclopropyl-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoate

¹H NMR (DMSO-d₆, 400 MHz) δ: 7.38 (s, 1H), 7.34-7.24 (m, 5H), 6.88 (d,J=8 Hz, 2H), 5.02 (s, 2H), 4.02-4.01 (m, 1H), 3.66 (s, 2H), 3.26 (s,2H), 2.73-2.71 (m, 2H), 2.58 (s, 2H), 2.41-2.37 (m, 1H), 2.27-2.24 (m,1H), 2.03-2.00 (m, 1H), 1.72 (s, 3H), 0.98-0.093 (m, 2H), 0.86-0.82 (m,2H).

Example 65(S)-3-(4-((3-((2-Nitro-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

¹H NMR (CD₃OD, 400 MHz) δ: 7.80 (s, 1H), 7.69 (s, 1H), 7.61-7.52 (m,3H), 7.30 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 5.17 (s, 2H), 4.54(s, 2H), 4.30 (s, 2H), 4.01-3.99 (m, 1H), 3.66 (s_((br)), 2H), 3.31-3.27(m, 2H), 2.69-2.58 (m, 2H), 1.80 (d, J=2.4 Hz, 3H)

Example 66(S)-3-(4-((3-((2-(Dimethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid compound with 2,2,2-trifluoroacetic acid

¹H NMR (CD₃OD, 400 MHz) δ: 8.00 (s, 1H), 7.54 (s, 1H), 7.45-7.42 (m,3H), 7.28 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.13 (s, 2H),4.01-3.99 (m, 3H), 3.74 (s, 2H), 3.14 (s, 6H), 3.10-3.07 (m, 2H),2.90-2.87 (m, 2H), 2.64-2.60 (m, 2H), 1.80 (d, J=2.4 Hz, 3H).

Example 67(S)-3-(4-((3-((2-Amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid compound with 2,2,2-trifluoroacetic acid

¹H NMR (CD₃OD, 400 MHz) δ: 8.10 (s, 1H), 7.67 (s, 1H), 7.62-7.54 (m,3H), 7.30 (dd, J=6.8, 1.6 Hz, 2H), 6.96 (d, J=6.8, 1.6 Hz, 2H), 5.17 (s,2H), 4.52 (s, 2H), 4.25 (s, 2H), 4.01-3.99 (m, 1H), 3.63 (s, 2H),3.09-3.05 (m, 2H), 2.70-2.58 (m, 2H), 1.80 (d, J=2.4 Hz, 3H)

Example 68(S)-3-(4-((3-((7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 8.59 (d, J=4 Hz, 1H), 7.87 (d, J=8 Hz, 1H),7.72 (s, 1H), 7.62-7.51 (m, 4H), 7.30 (dd, J=8.8, 2 Hz, 2H), 6.96 (d,J=8.8, 2 Hz, 2H), 5.17 (s, 2H), 4.57 (s, 2H), 4.49 (s, 2H), 4.01-3.97(m, 1H), 3.75-3.72 (m, 2H), 3.41-3.38 (m, 2H), 2.69-2.58 (m, 2H), 1.80(d, J=2.4 Hz, 3H).

Example 69(S)-3-(4-((3-((2-Cyclopropyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid compound with 2,2,2-trifluoroacetic acid

¹H NMR (CD₃OD, 400 MHz) δ: 7.66 (s, 1H), 7.60-7.52 (m, 2H), 7.30 (dd,J=6.8, 2 Hz, 2H), 6.90 (dd, J=6.8, 2 Hz, 2H), 6.50 (s, 1H), 5.17 (s,2H), 4.51 (s, 2H), 4.18 (s, 2H), 4.01-3.97 (m, 1H), 3.12-3.09 (m, 2H),2.67-2.60 (m, 2H), 1.80 (d, J=2.4 Hz, 3H), 1.00-0.97 (m, 2H), 0.66-0.64(m, 2H)

Example 70(S)-3-(4-((3-((2-Acetamido-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid compound with 2,2,2-trifluoroaceticacid

¹H NMR (CD₃OD, 400 MHz) δ: 7.68 (s, 1H), 7.62-7.54 (m, 3H), 7.30 (d,J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.17 (s, 2H), 4.56 (s, 2H), 4.40(s, 2H), 4.01-3.97 (m, 1H), 3.67 (s_((br)), 2H), 3.07-3.04 (m, 2H),2.69-2.58 (m, 2H), 2.20 (s, 3H), 1.80 (d, J=2.4 Hz, 3H).

Example 71(S)-3-(4-((3-((2-Ethyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid

¹H NMR (CD₃OD, 400 MHz) δ: 7.66 (s, 1H), 7.62-7.53 (m, 3H), 7.30 (d,J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.53 (s, 1H), 5.17 (s, 2H), 4.51(s, 2H), 4.51 (s, 2H), 4.20 (s, 2H), 4.01-3.97 (m, 1H), 3.57 (s_((br)),2H), 2.81-2.78 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.69-2.57 (m, 2H), 1.80(d, J=2.4 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).

Example 72(S)-3-(4-((3-((2-Acetyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid

¹H NMR (CD₃OD, 400 MHz) δ: 7.56-7.55 (m, 2H), 7.49-7.42 (m, 3H), 7.28(dd, J=6.8, 2 Hz, 2H), 6.93 (dd, J=6.8, 2 Hz, 2H), 5.12 (s, 2H), 4.09(s, 2H), 4.01-3.97 (m, 1H), 3.88 (s, 2H), 3.18-3.14 (m, 2H), 3.07-3.04(m, 2H), 2.66-2.56 (m, 2H), 2.50 (s, 3H), 1.79 (d, J=2.4 Hz, 3H)

Example 73(S)-3-(4-((3-((2-((Methylamino)methyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)benzyl)oxy)phenyl)hex-4-ynoicacid compound with 2,2,2-trifluoroacetic acid

¹H NMR (CD₃OD, 400 MHz) δ: 7.67 (s, 1H), 7.62-7.60 (m, 1H), 7.55-7.53(m, 2H), 7.30 (dd, J=6.8, 2 Hz, 2H), 7.03 (s, 1H), 6.96 (dd, J=6.8, 2Hz, 2H), 5.17 (s, 2H), 4.52 (s, 2H), 4.36 (s, 2H), 4.27 (s, 2H),4.01-3.98 (m, 1H), 3.62 (s_((br)), 2H), 3.24-3.21 (m, 2H), 2.71 (s, 3H),2.69-2.62 (m, 2H), 1.81 (d, J=2.4 Hz, 3H).

The novel compounds of the present invention can be formulated intosuitable pharmaceutically acceptable compositions by combining withsuitable excipients by techniques and processes and concentrations asare well known.

The compounds of formula (I or pharmaceutical compositions containingthem are useful as ligands of the GPR 40 receptor suitable for humansand other warm blooded animals, and may be administered either by oral,topical or parenteral administration.

The quantity of active component, that is, the compounds of formula (I)according to this invention, in the pharmaceutical composition and unitdosage form thereof may be varied or adjusted widely depending uponseveral factors such as the particular application method, the potencyof the particular compound and the desired concentration.

Biological Activity

The biological activity of the compounds of the present invention wastested in the following in vitro and in vivo models mentioned here.

Summary of the In Vitro Screening Protocol

To determine the EC₅₀ of the compounds on intracellular Ca²⁺ flux usinga fluorescent assay (FLIPR)

GPR40 expressing stable cells were seeded at 25,000 numbers/well. 50μL/well of assay buffer (20 mM HEPES+ 1×HBSS) was added to the cells andthe cells were cultured for 20 mm at 37° C. Cells were loaded with 50μL/well of Calcium 5 dye and cultured for 45 min at 37° C.

The cells were challenged with compounds at a top concentration of 1000nM (1:3 step down dilution—10 points). Intracellular Calcium flux wasassessed by use of Screen Works 3.1 tool and statistical analysis wascarried using Graph Pad Prism 4

Many of the compounds of the present invention demonstrated nanomolarpotency and significant % stimulation on intracellular Ca²⁺ flux whenmeasured using fluorescent (FLIPR) assay

The compounds exhibited potency in nanomolar range. (Table 1)

TABLE 1 In vitro EC50 values of the GPR 40 agonists of the presentinvention in FLIPR assay Compound EC₅₀(nM) 1 117 7 1.8 16 2.72 17 10.219 2.32 22 36.3

Promoter-Luciferase Assay to Measure GPR40 Activation

GPR40 activation was measured in HEK293 cells stably transfected withGPR40 cDNA (ChemiBrite cell lines from Millipore, US). These cells weretransiently transfected with a pGL2 (Promega Inc.) plasmid having a5×SRE sequence, cloned 5′ of a luciferase gene along with aβ-galactosidase plasmid as normalizing control. Briefly, 35000cells/well were seeded in a 96 well plates. After overnight incubationat 37° C. the cells were washed with PBS and transfected with the5×-SRE-Luciferase plasmid and the β-galactosidase plasmid. 6 h posttransfection, media was removed and replaced with fresh media withdifferent concentration of drugs and incubated for 16 more hours. Thecells were then lysed in 50 μL of Glo-Lysis buffer (Promega) for 30 minat room temperature. The cells were then centrifuged and lysates werecollected. Luciferase activity was measured by adding 100 μL ofluciferase substrate (Promega) in 20 μL of lysate and measuring theluminescence in luminometer. The β-galactosidase activity was alsomeasured by adding 20 μL of lysates with 20 μL of β-galactosidase buffer(Promega) and monitoring the absorbance at 415 nm. Luciferase valueswere divided by β-galactosidase values to normalize transectionefficiency (Table 2)

TABLE 2 In vitro EC50 values of the GPR 40 agonists of the presentinvention in Luciferase assay. Compound # EC₅₀ (nM) 1 7.5 7 1.49 8 11.810 16.9 12 5.6 13 0.8 14 0.8 15 4.6 16 4.6 17 4.7 18 8.8 19 0.2 20 2.721 2.8 22 31.46 23 5.3 24 0.7 26 4.1 30 4.5 31 9.7 32 4.8 35 204 38 17.839 1.7 40 8 43 7.3 44 4.8 46 6 47 9 50 20.8 51 3.0 55 56.5 58 3.7 60 5.661 12.6 62 3.0 63 4.4 64 1.2 65 1.6 68 11.9 69 0.8 71 0.4 72 2.3

Most of the compounds of the present invention were evaluated againstCYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 and there was nosignificant CYP inhibitory effect. The compounds did not showsignificant hERG binding at 10 μM.

In Vivo Efficacy Studies:

Primary Screening Protocol for GRP40 agonist test compounds in n-STZ ratmodel

Wistar rat pups of 1-2 day old injected with Streptozotocin (STZ) at 120mg/kg dose by intraperitoneal route. All pups allowed grow normally andat the age of 12-14 week they were screen for glucose intolerance byperforming the oral glucose tolerance test by tail clip method usingglucometer. Animals showing glucose intolerance were selected forevaluation of test compound. Three to seven days of rest period animalswere kept on overnight fasting. Next day morning blood glucose levelsmeasured using glucometer and animals were grouped such that theirpretreatment glucose levels were not significantly different betweengroups. Animals were administered with test compound and then then 15-60min after the compound administration “O” min blood glucose levels weremeasured and immediately glucose load at 2 g/kg was administered orally.Blood glucose levels were measured at 30, 60 and 120 min after glucoseload using by tail clip method using glucometer. Blood was alsocollected at 10 min after glucose load for measurement of insulinlevels. Glucose area under the curve (AUC) was calculated using GraphPad Prism software and % reduction in AUC-glucose vs vehicle treatedcontrol was calculated (Table 3).

TABLE 3 Efficacy of the GPR 40 agonist of the present invention in n-STZrat model Dose % improvement in AUC Compound (per oral) glucose vs.control 7 0.1 mg/Kg 30.4 1 mg/Kg 46.0 10 mg/Kg 57.0 10 0.1 mg/Kg 21.1 1mg/Kg 35.7 10 mg/Kg 45.0 16 1 mg/Kg 44.6 10 mg/Kg 59.6 17 1 mg/Kg 37.110 mg/Kg 44.7 60 1 mg/Kg 44 10 mg/Kg 47 64 1 mg/Kg 46 10 mg/Kg 47

In the n-STZ rat OGTT model the ED₅₀ of compounds 16, 60 & 64 has beenfound 0.05 mg/Kg, 0.04 mg/Kg & 0.09 mg/Kg respectively.

Few compounds have exhibited significant pharmacokinetics parameters inrats (Table 4)

TABLE 4 Pharmacokinetics parameters of compounds 16, 60, & 64 Parameters16 60 64 Dose (po) mg/Kg 3 3 3 T_(max) (h)   0.25 1 2 C_(max) (μg/mL)5.92 ± 2.10 7.77 ± 1.94 8.06 ± 2.19 AUC (0-t) 7.63 ± 1.27 52.52 ± 12.6282.42 ± 27.63 T_(1/2), po (h) 1.77 ± 0.42 5.45 ± 0.79 4.51 ± 0.61 Meanresidence time (h) 2.19 ± 0.31 5.74 ± 0.10 6.59 ± 0.93 iv dose (mg/Kg) 11 1 C₀(μg/mL) 5.02 ± 0.37 3.39 ± 0.33 10.16 ± 1.54  AUC (0-t) 3.18 ±0.40 18.61 ± 2.17  56.14 ± 4.35  (μg · h/mL) Vss (L/Kg) 0.34 ± 0.03 0.33± 0.01 0.16 ± 0.01 CL (mL/min./Kg) 5.26 ± 0.65 0.89 ± 0.10 0.27 ± 0.03T_(1/2), iv (h) 1.45 ± 0.12 5.57 ± 1.46 7.77 ± 1.07 Mean residence time(h) 1.09 ± 0.07 6.28 ± 0.77 10.07 ± 1.36  % F 83  93  45 

The compounds of formula (I) or pharmaceutical compositions containingthem are suitable for humans and other warm blooded animals, and may beadministered either by oral, topical or parenteral administration forthe treatment of various disease conditions associated withdyslipidemia, obesity etc.

The pharmaceutical composition is provided by employing conventionaltechniques. Preferably the composition is in unit dosage form containingan effective amount of the active component, that is, the compounds offormula (I) according to this invention.

The quantity of active component, that is, the compounds of formula (I)according to this invention, in the pharmaceutical composition and unitdosage form thereof may be varied or adjusted widely depending upon theparticular application method, the potency of the particular compoundand the desired concentration. Generally, the quantity of activecomponent will range between 0.5% to 90% by weight of the composition.

We claim:
 1. A compound(3S)-3-(4-((3-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)benzyl)oxy)phenyl)hex-4-ynoicacid or a pharmaceutically acceptable salt thereof.